Obsessive Compulsive Disorder (OCD) is often chronic, may produce marked impairment, and recent evidence suggests it may affect as many as 2-3% of the population at some point in their lives. The hypothesis that a disturbance in serotonin (5-HT) function is related to the etiology of OCD is based primarily on the anti-obsessive-compulsive (OC) efficacy of potent 5-HT reuptake inhibitors (e.g., fluvoxamine (FVX). However, despite apparently adequate drug treatment, many OCD patients (Pts) do not improve significantly. One explanation for this variable treatment response rate is that OCD may be neurobiologically heterogenous. For example, recent studies suggest a clinical and possibly genetic relationship between some forms of OCD and Tourett's Syndrome (TS), a disorder in which several lines of evidence implicate a pathophysiological role for brain dopamine (DA). We hypothesize that both the 5-HT and DA systems are involved in TS-spectrum OCD, i.e., OCD Pts with a personal or family history of TS or other chronic multiple tic disorder. The central goal of this project is to advance the neurobiology and treatment of OCD by 1-focusing on TS-spectrum OCD as a possible homogeneous form of OCD, and 2-investigating the relevance of intact 5-HT function to the mechanism of anti-OC drug action. The validity of TS-spectrum OCD as a distinct subtype will be assessed using a detailed clinical, family, drug treatment response profile that will be obtained in approximately 80 adult OCD Pts. There are 3 parts to the project: Study I. Pts will be divided prospectively into two putative subtypes (TS- spectrum and Non-TS-spectrum OCD) on the basis of clinical history and direct, structured interviews of family members (approx 400 interviews). Study II. Next, the Pts will enter an 8-week single-blind trial with the potent and selective 5-HT reuptake inhibitor FVX. Pts with an incomplete response to FVX alone (-N=64) will be randomized to a 4-week double-blind trial of FVX in combination with the DA2-antagonist haloperidol (HAL) or placebo (:LA). It is predicted that the TS spectrum OCD subgroup will preferentially respond to the addition of low dose neuroleptic. Study III. Finally, OCD Pts improved on drug will be acutely depleted of the 5-HT precursor tryptophan (TRP) (via a competing large neutral amino acid drink) in a double-blind, placebo-controlled design.